Alzheimer's disease (AD) is a major and growing health problem currently facing this country. Research which suggests that treatments may be more effective when administered early, as well as recent attempts to develop a vaccine for AD, make the identification of preclinical markers, the overal goal of this study, critical. In the previous funding period, we recruited 100 adult offspring of autopsy-confirmed late-onset familial AD cases from multiplex families with extensively characterized pedigrees, currently enrolled in a genetic study of AD and part of the NIMH Genetics Initiative sample developed here at Johns Hopkins, and matched controls. These indiviudals have been evaluated twice, three years apart. The study has examined memory function, structural and functional brain imaging, and selected biomarkers. Analysis of Time 1 data, while showing no differences on cognitive testing, did reveal a) functional brain differences between the at-risk and control samples, with key differences seen in the temporal and frontal lobes as well as the cinguate and thalamus and b) structural differences, namely decreased white matter volume in the at-risk. In addition, an analysis of offspring from families with evidence of maternal transmission and those with evidence of paternal transmission found distinct functional patterns. These findings have now been published. Analysis of Time 2 data has revealed the following: a) significant decline in long term memory retention in the at-risk, b) continued decline in white matter volume in the at-risk; c) unchanged fMRI bold response pattern for males but significant change over time for at-risk females; d) significantly greater area of BOLD activation in the at-risk as shown by correlation matrices, e) significant decline on cognitive testing for a subset who now meet criteria for mild cognitive impairment (MCI). Inspection of the Time 1 data indicates that the MCI cases are distinguished by elevated levels of vitamin A, smaller volumes of the left frontal lobe and thalamus bilaterally, and reduced fMRI activation in the cingulate and right frontal gyrus. In this next funding period the aim is to continue the study of cognition, structural and functional neuroimaging and biomarkers in this sample, collecting two additional time points. Specifically we will examine cognitive performance on tests of memory and learning, generalized and regional brain measures from conventional MRI, and changes in activation with fMRI paradigms designed to activate brain regions known to show early changes in AD, including the temporal and parietal lobes as well as the posterior cingulate. New collaborations will allow us to examine cortical thickness and white matter integrity through the use of diffusion tensor imaging (DTI). We will correlate APOE status and linkage to chromosome 10q with these measures. The results of this study will provide information on the identification of preclinical markers for late-onset AD. They may also assist in refining phenotypes for AD and thus aid the search for genes implicated in the development of AD. It is hoped this work will prove valuable as future interventions for AD are developed.